Halogenation Strategies In Natural Product Biosynthesis

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Halogenation Strategies In Natural Product Biosynthesis Christopher S. Neumann, Danica Galonić Fujimori, Christopher T. Walsh Chemistry & Biology Volume 15, Issue 2, Pages 99-109 (February 2008) DOI: 10.1016/j.chembiol.2008.01.006 Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 1 Representative Natural Products with Halogen-Dependent Bioactivity Chemistry & Biology 2008 15, 99-109DOI: (10.1016/j.chembiol.2008.01.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 2 Oxidative Halogenation by Haloperoxidases (A) Formation of hypochlorous acid by heme Fe-dependent chloroperoxidase. (B) Formation of vanadium-bound hypobromite by V-BPO. (C) Chloronium-mediated cyclizations catalyzed by V-CPOs to produce a chlorinated napyradiomycin derivative. The chlorine on the benzoquinone core is likely incorporated via a flavin-dependent halogenase. Chemistry & Biology 2008 15, 99-109DOI: (10.1016/j.chembiol.2008.01.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 3 Chemistry of Flavin-Dependent Halogenases (A) Regioselective chlorination of tryptophan by FAD-dependent halogenases and dichlorination of pyrrolyl-S-PltL by PltA. (B) Mechanism of halogenation by RebH. Flavin-generated hypochlorous acid is trapped by the enzyme as lysine chloramine before tryptophan halogenation. Chemistry & Biology 2008 15, 99-109DOI: (10.1016/j.chembiol.2008.01.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 4 Chemistry of Fe(II)/αKG-Dependent Halogenases (A) Representative biosynthetic transformations. (B) Catalytic cycle for Fe-dependent halogenases. Inset graph shows time-dependent 318 nm absorbance of the reactive Fe(IV)–oxo species in the presence of L-Aba-S-CytC2 (red), with extended half-life in the presence of d3-L-Aba-S-CytC2 substrate (blue). Chemistry & Biology 2008 15, 99-109DOI: (10.1016/j.chembiol.2008.01.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 5 Halogenation of Natural Products via Halide Anion (A) Incorporation of chloride into 5′-chloro-5′-deoxyadenosine in the biosynthesis of salinosporamide A. (B) Monochlorinated enediyne-derived cyanosporasides and sporolides. (C) Proposed mechanism for nonenzymatic halide incorporation into enediyne natural products. Chemistry & Biology 2008 15, 99-109DOI: (10.1016/j.chembiol.2008.01.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 6 New Opportunities for Enzymatic Halogenation (A) Alternative hypotheses, invoking FADH- or Fe-dependent halogenases, for the formation of the alkynyl bromide functionality in jamaicamide. (B) Natural products with novel halogenated or halogen-derived functional groups. Chemistry & Biology 2008 15, 99-109DOI: (10.1016/j.chembiol.2008.01.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 7 Alternative Strategies for Halogenase-Based Discovery (A) Discovery of novel structures following PCR amplification of halogenases from potential producer strains. (B) Discovery of kutzneride gene cluster following PCR amplification of predicted halogenases. Chemistry & Biology 2008 15, 99-109DOI: (10.1016/j.chembiol.2008.01.006) Copyright © 2008 Elsevier Ltd Terms and Conditions